NAD(P)H:quinone oxidoreductase 1 (NQO1; EC 1.6.99.2; originally called DT-diaphorase), is a highly inducible, obligate two-electron reductase present in a wide variety of mammalian tissues. The enzyme can detoxify both natural and synthetic xenobiotics and, when expressed in high levels, can scavenge intracellular superoxide.
NQO1 has been exploited in cancer therapy as a bioactivating enzyme for various antitumor quinones. Using this approach, cancer cells expressing high levels of NQO1 accumulate greater levels of these activated antitumor quinones, which in turn kill the cell. Recently however, the contradictory approach of inhibiting NQO1 has been shown to lead to the inhibition of cell growth and to cell death following the increased production and accumulation of intracellular superoxide. This presents a new treatment modality for mammalian tumors expressing NQO1 wherein inhibition of NQO1 leads to cell death through intracellular superoxide accumulation.
Studies showing the accumulation of superoxide following NQO1 inhibition were conducted with the NQO1 inhibitor, dicumarol. Dicumarol is the only commercially-available inhibitor of NQO1. Unfortunately, dicumarol is a non-specific, competitive inhibitor known to have many ancillary effects, including the inhibition of many dehydrogenase and reductase enzymes such as glutathione-S-transferase and glutathione peroxidase, UDP-glucuronosyltransferase, and a variety of stress-activated protein kinases, particularly at high doses. Dicumarol has also been reported to inhibit mitochondrial oxidative phosphorylation and NFkB activation. Thus, there has been a search for compounds that specifically inhibit NQO1.